CN114206354B - Composition for protecting and repairing the Blood Brain Barrier (BBB) - Google Patents

Composition for protecting and repairing the Blood Brain Barrier (BBB) Download PDF

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CN114206354B
CN114206354B CN202080047142.7A CN202080047142A CN114206354B CN 114206354 B CN114206354 B CN 114206354B CN 202080047142 A CN202080047142 A CN 202080047142A CN 114206354 B CN114206354 B CN 114206354B
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brain barrier
blood brain
composition
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CN114206354A (en
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丹尼斯·巴里托
米里亚姆·贝尔诺丹
奥马尔·图扎尼
杰尔姆·图坦
雅辛·科和利夫
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Dan NisiBalituo
ORGANES TISSUS REGENERATION REPARATION REMPLACEMENT-OTR3
Centre National de la Recherche Scientifique CNRS
Universite de Caen Normandie
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Dan NisiBalituo
ORGANES TISSUS REGENERATION REPARATION REMPLACEMENT-OTR3
Centre National de la Recherche Scientifique CNRS
Universite de Caen Normandie
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/737—Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/717—Celluloses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/721—Dextrans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Abstract

The present invention relates to pharmaceutical compositions for use as a medicament, in particular for protecting the blood brain barrier and/or repairing and/or restoring the blood brain barrier. The invention has particular application in the therapeutic, pharmaceutical and veterinary fields.

Description

Composition for protecting and repairing the Blood Brain Barrier (BBB)
Technical Field
The present invention relates to pharmaceutical compositions for use as a medicament, in particular for protecting the blood brain barrier.
The invention also relates to a pharmaceutical composition for use as a medicament, in particular for repairing and/or restoring the blood brain barrier.
The present invention relates to pharmaceutical compositions for use as a medicament, in particular for protecting and/or repairing and/or restoring the blood brain barrier.
The invention has particular application in the therapeutic, pharmaceutical and veterinary fields.
In the following description, reference numerals in brackets () point to a list of references given at the end of the text.
Background
The Blood Brain Barrier (BBB), also known as the blood brain barrier or blood brain barrier, consists of a monolayer of endothelial cells in the brain microvasculature. These endothelial cells have tight junctions between them, thus limiting paracellular and transcellular exchange between the blood compartment and the parenchymal compartment. Endothelial cells are surrounded by basement membrane, astrocyte feet and pericytes, thereby enhancing the BBB (Sharif et al, 2018[16 ]). The basal layer below the brain endothelium actively participates in the dynamics of the BBB, consisting of 3 layers. The first layer is synthesized by endothelial cells and is characterized by the presence of laminin 4 and 5. The second layer is characterized by the presence of laminin 1 and 2, synthesized by astrocytes. The third layer is characterized by the presence of collagen IV, between the first two layers and formed by two cell types. These three layers also consist of different types of collagen, glycoproteins and proteoglycans, in particular Heparan Sulfate Proteoglycans (HSPG) (Cardoso et al, 2010[4 ]).
The basal lamina also contains a number of proteins, metalloproteinases (MMPs) and their inhibitors, which are involved in the dynamic regulation of the BBB under physiological and pathological conditions.
The BBB protects neurons from factors present in the systemic circulation and maintains the internal environment of the central nervous system, which is necessary for good synapse and neuronal function (Sharif et al, 2018[16 ]).
Alterations in BBB have been reported in a number of brain diseases, such as Alzheimer's disease, parkinson's disease, huntington's disease, multiple sclerosis, cerebral Vascular Accidents (CVA), chronic traumatic encephalopathy, and brain infections (Abdulahi et al, 2018[1]; sweeney et al, 2018[19]; erickson and Banks 2018[5 ]). The BBB is also impaired in the presence of brain tumors and after brain irradiation as part of radiotherapy (Katherine Elizabeth warren, 2018[22 ]). Disruption of the BBB allows neurotoxic agents derived from blood, cellular and microbial pathogens to flow into the brain and are associated with inflammatory and immune responses, which can initiate and exacerbate several pathways of neuronal death (Sharif et al, 2018[16 ]).
In the prior art, there are therapeutic regimens and/or strategies aimed at protecting BBB structural components: tight junctions and cellular receptors; or against the cause of its permeability: inflammation; oxidizing; activation of MMP (Sifat et al, 2017[17 ]). However, these treatment regimens and/or strategies do not demonstrate any true efficacy and/or significant therapeutic effects, particularly for the protection of the BBB.
Other strategies for protecting the BBB are also contemplated. For example, the prior art patent document describes targeting cell signaling pathway molecules (delta-PKC) (patent application US20090062208 A1); a transcription factor (HMGB 1) (application WO2018207792A 1), an S100B protein (patent document CN 101632728B), or even a cell ligation associated with the BBB (Claudin-5) (patent document CN 105148276B). However, none of these methods and/or strategies have led to therapeutic or clinical use to date. Furthermore, in the prior art, no known product is used directly as a protector or to facilitate the restoration of the BBB. In other words, there is currently no compound and/or pharmaceutical composition capable of protecting and/or repairing and/or restoring the blood brain barrier.
Thus, there is a real need in the art to find a compound and/or composition that makes it possible to protect the BBB, for example from damage and/or alterations due to pathologies such as the brain and/or treatments (such as chemotherapy and/or radiotherapy).
There is also a real need in the art to find a compound and/or composition that allows to repair alterations and/or damages of the BBB, for example due to alzheimer's disease, parkinson's disease, huntington's disease, multiple sclerosis, after cerebrovascular accident (CVA), traumatic brain diseases (e.g. chronic brain infections, e.g. viral or bacterial meningitis), alterations and/or damages due to e.g. brain tumor presence and/or treatment (e.g. chemotherapy and/or radiotherapy of the brain).
There is also a real need in the art to find a compound and/or composition that allows the functional recovery of the BBB, for example after damage and/or deterioration of said BBB.
Disclosure of Invention
The present invention aims at meeting these needs by providing a pharmaceutical composition for its use or as a medicament for protecting and/or repairing and/or restoring the blood brain barrier, preferably its functionality, said composition comprising-a biocompatible polymer of the general formula (I)
AaXxYy(I)
Wherein:
a represents a monomer, and the monomer is a monomer,
x represents R 1 COOR 2 Radicals or-R 9 (C＝O)R 10
Y represents a compound corresponding to the formula-R 3 QSO 3 R 4 、-R 5 NSO 3 R 6 、-R 7 SO 3 R 8 An O or N-sulfonate group of one of (c), wherein:
R 1 、R 3 、R 5 and R is 9 Independently represents an aliphatic hydrocarbon chain, optionally branched and/or unsaturated and which optionally contains one or more aromatic rings, except for benzylamine and benzylamine sulfonate, R 2 、R 4 、R 6 And R is 8 Independently represent a hydrogen atom or M + Cation, and R 7 And R is 10 Independently represent a bond, an optionally branched and/or unsaturated aliphatic hydrocarbon chain,
a represents the number of monomers and is defined as,
x represents the degree of substitution of monomer A by the X group,
y represents the degree of substitution of monomer A by the Y group.
The present invention aims at meeting these needs by providing a pharmaceutical composition for use as a medicament for protecting and/or repairing and/or restoring the blood brain barrier, preferably its functionality, said composition comprising
-biocompatible polymers of the general formula (I)
AaXxYy(I)
Wherein:
a represents a monomer, and the monomer is a monomer,
x represents R 1 COOR 2 Radicals or-R 9 (C＝O)R 10
Y represents a compound corresponding to the formula-R 3 QSO 3 R 4 、-R 5 NSO 3 R 6 、-R 7 SO 3 R 8 An O or N-sulfonate group of one of (c), wherein:
R 1 、R 3 、R 5 and R is 9 Independently represents an aliphatic hydrocarbon chain, optionally branched and/or unsaturated and which optionally contains one or more aromatic rings, except for benzylamine and benzylamine sulfonate, R 2 、R 4 、R 6 And R is 8 Independently represent a hydrogen atom or M + Cation, and R 7 And R is 10 Independently represent a bond, an optionally branched and/or unsaturated aliphatic hydrocarbon chain,
a represents the number of monomers and is defined as,
x represents the degree of substitution of monomer A by the X group,
y represents the degree of substitution of monomer A by the Y group.
Advantageously, the inventors have surprisingly shown that the use of biocompatible polymers according to the invention advantageously makes it possible to consolidate, strengthen and/or repair the Blood Brain Barrier (BBB).
In particular, the inventors have unexpectedly shown that the use of the biocompatible polymers of the invention advantageously allows to repair and/or strengthen and/or restore the Blood Brain Barrier (BBB) when the BBB is altered, for example, when inflammation and/or damage occurs and/or any alteration known to a person skilled in the art, whatever the cause or source thereof.
The inventors have also surprisingly and unexpectedly shown that the use of the polymers according to the invention advantageously makes it possible to accelerate and improve the functional recovery of the Blood Brain Barrier (BBB). Furthermore, the inventors have surprisingly and surprisingly shown that the use of the polymers according to the invention also makes it possible to accelerate and/or improve functional motor and cognitive recovery when changes in the BBB have an effect on motor and/or cognitive function.
As used herein, protection of the blood brain barrier is understood to mean, for example, improvement of the basement membrane structure of the blood brain barrier and/or stimulation of endothelial cells of the blood brain barrier and/or strengthening of the tight junctions of the blood brain barrier. Advantageously, the protection of the blood-brain barrier allows, for example, to protect the latter from external attacks, for example from ionizing radiation, for example from X-rays, gamma rays, from isotopic compounds, for example from xenobiotic compounds, various toxins and pathogens. The protection of the blood brain barrier may also maintain homeostasis of the central nervous system, such as regulation of ion flow, and/or regulation of molecular and cellular flow, particularly between the blood compartment and the central nervous system. In the case of damage and permeability of the barrier, these flows may be detrimental to the central nervous system.
As used herein, repair of the blood-brain barrier is understood to mean, for example, the reformation and/or improvement of the blood-brain barrier structure, for example, when the structure of the barrier has been altered, for example, due to damage, external aggressions, such as pathogens, diseases, due to inflammation and/or any event known to those skilled in the art, capable of altering and/or modifying the structure and/or function of the blood-brain barrier. This may be, for example, accelerating the healing of blood brain barrier lesions, reducing inflammation of the blood brain barrier, healing and/or improving the basement membrane of the blood brain barrier and/or endothelial cells of the blood brain barrier and/or tight junctions of the blood brain barrier.
As used herein, restoration of the blood brain barrier is understood to mean structural repair and/or reformation of the blood brain barrier and restoration/improvement of blood brain barrier function, such as restoration/improvement of blood brain barrier permeability and/or any physiological function of the blood brain barrier.
In this document, monomers are understood to mean, for example, monomers selected from the group comprising sugars, esters, alcohols, amino acids or nucleotides.
In the present invention, the monomers A constituting the structural units of the polymer of formula I may be identical or different.
In the present invention, monomer a may independently be a monomer of the formula:
wherein R is 11 And R is 12 Independently represent an oxygen atom, an optionally branched and/or unsaturated aliphatic hydrocarbon chain, a heteroaryl group independently comprising one or more oxygen and/or nitrogen atoms, an aldehyde function, a carboxylic acid group, a diol, a substituted diol, a compound of formula-R 13 -(X)n-R 14 Wherein R is a group of 13 Represents optionally branched and/or unsaturated C 1 -C 4 Aliphatic carbon chains, X represents a heteroatom selected from oxygen and nitrogen, is an integer from 1 to 4, and R 14 Heteroaryl groups, which are hydrogen atoms, optionally branched and/or unsaturated aliphatic hydrocarbon chains, independently comprising one or more oxygen atoms and/or nitrogen, aldehyde functions, carboxylic acid groups, diols, substituted diols.
In the present invention, the combination of monomers may form a polymeric backbone of the nucleic acid or protein type, for example polymeric backbones of the polyester, polyol, polysaccharide nature.
In the present invention, among the polyesters, they may be, for example, biosynthetic or chemically synthesized copolymers, such as aliphatic polyesters or copolymers of natural origin, such as polyhydroxyalkanoates.
In the present invention, the polysaccharide and derivatives thereof may be of bacterial, animal, fungal and/or plant origin. For example, they may be single-chain polysaccharides, such as polydextrose, e.g. dextran, cellulose, beta-dextran, or other monomers comprising more complex units, such as xanthan gum, e.g. glucose, mannose and glucuronic acid or also glucuronic acid and glucuronic acid glycans.
In the present invention, the plant-derived polysaccharide may be single-chain, such as cellulose (glucose), pectin (galacturonic acid), fucan, starch, or more complex such as alginate (guluronic acid and mannuronic acid).
In the present invention, the polysaccharide of fungal origin may be, for example, a steryl glucan.
In the present invention, the polysaccharide of animal origin may be, for example, chitin or chitosan (glucosamine).
In the present invention, the monomers a constituting the essential elements of the polymer of formula I may advantageously be identical.
In the present invention, the monomer a constituting the essential element of the polymer of formula I may advantageously be glucose.
The amount of monomer a defined by "a" in formula (I) may be such that the mass of the polymer of formula (I) is about 2,000 to 6,000 daltons, for example, which corresponds to at least 10 glucose monomers. For example, the mass of the polymer of formula (I) may be about 3,000 to 6,000 daltons, e.g., which corresponds to 12 to 20 glucose monomers.
The amount of monomer a defined by "a" in formula (I) may also be such that the mass of the polymer of formula (I) is less than about 2,500,000 daltons (which corresponds to 7,000 glucose monomers). Advantageously, the mass of the polymer of formula (I) may be from 3,000 to 250,000 daltons, for example from 3,000 to 6,000 daltons, or for example from 20,000 to 250,000 daltons, or for example from 75,000 to 150,000 daltons.
In the present invention, in the case of-R representing X 1 COOR 2 In the radicals, R 1 May be C 1 -C 6 Alkyl, e.g. methyl, ethyl, butyl, propyl, pentyl, preferably methyl, R 2 May be a bond, C 1 -C 6 Alkyl radicals, such as the methyl, ethyl, butyl, propyl, pentyl, radicals R 21 R 22 Wherein R is 21 Is an anion, R 22 Is a cation selected from the group of alkali metals.
Preferably, the group X is of formula-R 1 COOR 2 Wherein R is a group of 1 Is methyl-CH 2 -and R 2 Is a group R 21 R 22 Wherein R is 21 Is anionic and R 22 Is a cation selected from the group of alkali metals, preferably the group X is of the formula-CH 2 -COO - Or a carboxymethyl group.
In the present invention, in the group-R representing X 9 (C＝O)R 10 Wherein R is 9 May be C 1 -C 6 Alkyl, e.g. methyl, ethyl, butyl, propyl, pentyl, preferably methyl, and R 10 May be a bond, C 1 -C 6 Alkyl groups such as methyl, ethyl, butyl, propyl, pentyl, hexyl.
The degree of substitution of all monomers a defined by "X" in formula (I) by X groups may be from 10 to 150%, from 40 to 80%, preferably about 50% or 60%.
In the present invention, the compound represented by the following formula-R 3 OSO 3 R 4 、-R 5 NSO 3 R 6 、-R 7 SO 3 R 8 In the group of one of them and representing a Y group, R 3 May be a bond, C 1 -C 6 Alkyl, e.g. methyl, ethyl, butyl, propyl, pentyl, preferably methyl, R 5 May be a bond, C 1 -C 6 Alkyl, e.g. methyl, ethyl, butyl, propyl, pentyl, preferably methyl, R 7 May be a bond, C 1 -C 6 Alkyl, e.g. methyl, ethyl, butyl, propyl, pentyl, preferably methyl, R 4 、R 6 And R is 8 Can independently be a hydrogen atom or M + Cations, e.g. M + May be an alkali metal.
Preferably, the Y group is of formula-R 7 SO 3 R 8 Wherein R is a group of 7 Is a bond and R 8 Is an alkali metal selected from the group consisting of lithium, sodium, potassium, rubidium, and cesium. Preferably, the Y group is-SO 3 - Radicals, -SO 3 - Na + 。
The degree of substitution of all monomers a defined by "Y" in formula (I) by Y groups may be from 10 to 170%, from 30 to 150%, from 55 to 160%, from 55 to 85%, from 120 to 160%, preferably about 70%, 140% or 150%.
In the present invention, the definition of the degree of substitution above is 100% of the degree of substitution "X" means that each monomer a of the polymer of the present invention statistically contains an X group. Similarly, a degree of substitution "Y" of 100% means that each monomer of the polymer of the invention contains statistically Y groups. The degree of substitution greater than 100% reflects the fact that: each monomer statistically contains more than one group of the type considered; conversely, a degree of substitution of less than 100% reflects that each monomer statistically contains less than one group of the type considered.
The polymer may also contain chemical functional groups other than X and Y, designated Z.
In the present invention, the Z groups may be the same or different and may be independently selected from the group consisting of amino acids, fatty alcohols, ceramides or derivatives thereof, or addressed nucleotide sequences, antibodies, antibody fragments.
The Z groups may also represent the same or different active agents. These may be, for example, therapeutic agents, diagnostic agents, anti-inflammatory agents, antimicrobial agents, antibiotics, growth factors, enzymes, antioxidant compounds, polyphenols, tannins, anthocyanins, lycopene, terpenes and resveratrol. In the present invention, the Z group may advantageously be a saturated or unsaturated fatty acid. It may be, for example, a fatty acid selected from the group comprising: acetic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachic acid, behenic acid, lignoceric acid, cerotic acid, myristoleic acid, palmitoleic acid, hexadecenoic acid, oleic acid, elaidic acid, trans-iso-oleic acid, linoleic acid, elaidic acid, alpha-linolenic acid, gamma-linolenic acid, dihomo-gamma-linolenic acid, arachidonic acid, eicosapentaenoic acid, elaidic acid or docosahexaenoic acid. Preferably, the fatty acid is acetic acid.
In the present invention, the Z group may advantageously be an amino acid of the L or D series selected from the group comprising alanine, asparagine, an aromatic chain such as tyrosine, phenylalanine, tryptophan, thyroxine or histidine. Preferably, the amino acid is phenylalanine.
In the present invention, the Z group may be an antioxidant, such as vitamins A, C, E, B, B6, glutathione, selenium, polyphenols, such as catechins, such as green tea, flavonoids, tannins, anthocyanins, such as red fruits, lycopene, terpenes, and resveratrol.
In the present invention, the Z group may be an anti-aging compound, such as retinoid, allantoin.
In the present invention, the Z group may be an antibody, an antibody fragment, such as a Fab fragment. They may be, for example, antibodies and/or fragments of addressing antibodies, for example antibodies and/or antibody fragments capable of targeting the blood brain barrier.
Advantageously, the Z groups may impart additional biological or physicochemical properties to the polymer. For example, the Z groups may increase the solubility or lipophilicity of the polymer, e.g., allowing for better diffusion or tissue penetration.
Advantageously, the Z groups may impart additional biological or physicochemical properties to the polymer. Thus, the polymers of the present invention, for example when the Z groups are selected from antioxidant compounds, anti-aging compounds, can advantageously deliver these compounds and thus provide additional and/or complementary biological effects.
The polymer in which Z is present may correspond to formula II below: aa x Yy Zz (II), wherein A, X, Y, a, x, y is defined above, and Z represents the degree of substitution of the Z group.
In the present invention, the degree of substitution of the Z group represented by "Z" may be 1% to 50%,10% to 25%, preferably equal to 15%, 20% or 25%.
X, Y and Z groups can be independently linked to monomer A and/or independently of each other. When at least one of the X, Y and Z groups is independently attached to a X, Y and Z group different from the first, one of the X, Y or Z groups is attached to monomer a.
Thus, the Z group may be covalently linked directly to monomer A or to the X and/or Y groups.
In the present invention, the Z group may also be conjugated to the polymer of formula Aaxxyy by a bond other than a covalent bond, for example by an ionic bond, for example by ionic interactions, hydrophilic bonds or hydrophobic bonds. The polymers of the invention may then constitute a Z-vectorized system.
In the present invention, the polymer may be, for example, a polymer selected from the group comprising compounds OTR4120, OTR41201, OTR41202, OTR41203, OTR41205, OTR41210, OTR41301, OTR41302, OTR41303, OTR41305, OTR41310, OTR 3131.
Herein, the polymer may be, for example, a polymer selected from the group comprising compounds OTR41201, OTR41202, OTR41203, OTR41205, OTR41210, OTR4120, OTR4122, OTR4125, OTR41301, OTR41302, OTR41303, OTR41305, OTR41310, OTR3131, OTR4132, OTR4135, OTR415 having the characteristics described in table 1 below.
Table 1: aaxxyy (I) and Aaxxyyzz (II) families, wherein A is glucose (MW 180D) and X is carboxymethyl (MW 58D) Y: SO (SO) 3 - (MW 80D) and Z are acetate (MW 43D) or phenylalanine (MW 165D).
In the present invention, the composition may comprise the biocompatible polymer at a concentration of 0.1 to 100 μg/ml by weight relative to the volume of the composition. For example, the composition may comprise the biocompatible polymer at a concentration of 1 to 10 μg/ml by weight relative to the total volume of the composition.
In the present invention, the composition may be formulated and/or adjusted according to its application. For example, for parenteral administration, the composition may be administered at a frequency of once weekly administration to deliver a biocompatible polymer dose of 0.01 to 5mg/kg body weight, preferably 0.1 to 1.5mg/kg body weight.
For example, for oral administration, the composition may be administered at a daily or weekly frequency to deliver a biocompatible polymer dose of 0.1 to 5mg/kg body weight, preferably 0.01 to 1.5 mg/kg.
For sublingual administration, uptake may be daily or twice weekly, and is between 0.5 μg/kg and 100 μg/kg.
For example, for intra-arterial administration, the biocompatible polymer may be at a concentration of 0.1 to 100 μg/ml by weight, preferably 1 to 20ml, relative to the total volume of the composition.
Advantageously, when the composition and/or polymer is administered by an intra-arterial route, administration may be performed first in the brain, for example by a route in the internal carotid artery.
For example, for intracranial injection, the biocompatible polymer may be at a concentration of 0.1 to 100 μg/ml by weight, preferably 5 to 20 μl, relative to the total volume of the composition.
Advantageously, when the composition and/or polymer is administered by the intracranial route, administration can be performed simultaneously or sequentially in different intracranial regions.
For example, for intraventricular or intrathecal injection, the volume administered may include 5 μl to 2ml, such as 500 μl, for example 2ml. For example, for intraventricular or intrathecal injection, the volume administered may be an equal volume, e.g., up to 2ml. For example, the volume administered may be as described in Marks et al, 2008[10], raffi et al, 2014[13] and/or Blaney et al, 2004[3 ].
For oral administration, the biocompatible polymer may be dosed, for example in the form of a pill or capsule, at a dose of 0.0001 to 5mg/kg body weight.
For oral administration, for example in the form of pills or capsules, it can be taken daily.
According to the present invention, the biocompatible polymer may have a molecular weight of 3,000 to 2,500,000 daltons.
For example, the biocompatible polymer may have a molecular weight of 3,000 to 6,000 daltons, 6,000 to 2,500,000 daltons, preferably 20,000 to 250,000 daltons, for example 75,000 to 150,000 daltons.
Advantageously, the molecular weight of the biocompatible polymer present in the composition may be selected according to the route of administration and the frequency of administration of the composition. For example, for injection by an intravascular route, such as intra-arterial, the molecular weight of the biocompatible polymer may be 3,000 to 200,000 daltons, depending on the level of damage to the blood brain barrier damage, preferably 3,000 to 150,000 daltons.
Advantageously, the molecular weight of the biocompatible polymer present in the composition may be selected according to the deterioration and/or state of the blood brain barrier.
For example, when the blood brain barrier experiences significant structural changes, such as induction of damage to the blood brain barrier by high permeability, the biocompatible polymer may have a molecular weight of 3,000 to 200,000 daltons, preferably 70,000 to 150,000 daltons.
Advantageously, the molecular weight of the biocompatible polymer may be adjusted after and/or in accordance with the progressive repair of the blood brain barrier. For example, when the blood brain barrier exhibits a significant structural change, the biocompatible polymer may have a molecular weight of 3,000 to 200,000 daltons, preferably 70,000 to 150,000 daltons. The molecular weight used may then be reduced, for example from 3,000 to 100,000 daltons, preferably from 10,000 to 70,000 daltons.
According to the invention, the composition may further comprise a hydrogel.
In this context, hydrogel is understood to mean any suitable hydrogel known to the person skilled in the art. For example, it may be a hydrogel selected from the group of biocompatible hydrogels comprising hyaluronic acid or a derivative thereof for filling the brain space after injury. For example, it may be Vladimir A.Kornev et al, hydrogel-assisted neuroregeneration approaches towards Brain injury therapy, A state-of-the-art review.computer and Structural Biotechnology Journal 16j.csbj.2018.10.011[24], and/or Gopalakrishenan A, shankarappa SA, rajanikant GK.Hydrogel Scaffoldes: towards Restitution of lschemic Stroke-lnjured Brain 2019Feb;10 The hydrogel described in 1-18[25 ].
Herein, the composition may comprise a hydrogel concentration of 0.1% to 5%, preferably 0.5% to 2.5% by weight of the hydrogel.
According to the invention, the composition may comprise hyaluronic acid and/or at least one hydrogel and/or a mixture thereof.
In this context, "hyaluronic acid" is understood to mean any hyaluronic acid known to the person skilled in the art, such as a non-sulfated linear glycosaminoglycan consisting of repeating units of D-glucuronic acid and N-acetyl-D-glucosamine. It may be Hyaluronic Acid (HA), for example in acid form or in the form of a salt of cross-linked hyaluronic acid (hyaluronate). HA is a non-sulfated linear glycosaminoglycan composed of repeating units of D-glucuronic acid and N-acetyl-D-glucosamine (Tammi R., agren UM., tuhkanen AL., tammi M.Hyaluronan metacan in skin. Progress in Histochemistry & cytochemistry.29 (2): 1-81,1994[26 ]). It may be, for example, hyaluronic acid having an average molecular weight fraction of 5,000 to 3,000,000 daltons, preferably 50,000 to 2,000,000 daltons. In the case of the present invention, hyaluronic acid may be obtained by any method known to those skilled in the art. For example, these may be the following methods: magazine Hyaluronan fragments an information-rich system (R.Stern et al European Journal of Cell Biology (2006) 699-715[27 ]). It may also be natural or modified hyaluronic acid, commercially available, whatever their name and/or molecular weight, for example chosen from Hyactive CPN; cristalhyal; nutra HA; oligo HA; d Factor; hyaluderm; juvelift; restylane; commercial hyaluronic acid of Revitacare; this list is not exhaustive. It may also be hyaluronic acid sold by Contipro (https:// www.contipro.com/portfolio/manufacturing-of-anti-forming-cosmic-raw-materials/HyActive ") and/or Givaudan (https:// www.givaudan.com/fragranties/active-reliability/products/creature%C2% AE-range).
Herein, the composition may comprise hyaluronic acid at a concentration of 0.1% to 5% by weight relative to the total weight of the composition. For example, the composition may comprise hyaluronic acid at a concentration of 0.5% to 2.5% by weight relative to the total weight of the composition.
Herein, the hydrogel composition may be formulated for administration by a direct intracranial route, and for local intracranial injection, in particular by an intra-arterial route, the composition may comprise hyaluronic acid at a concentration of 1 to 10mg/ml by weight relative to the total volume of the composition.
In this context, the term "pharmaceutical composition" is understood to mean any form of pharmaceutical composition known to the person skilled in the art. In this context, the pharmaceutical composition may be, for example, an injectable solution. It may be, for example, an injectable solution, for example for local or systemic injection, for example in physiological serum, in an injectable dextrose solution, in the presence of excipients such as dextran, for example in concentrations known to the person skilled in the art, for example from one microgram to several milligrams per ml. The pharmaceutical composition may be, for example, a medicament for oral administration selected from the group consisting of liquid formulations, effervescent oral dosage forms, oral powders, multiparticulate systems, orodispersible dosage forms.
For example, when the pharmaceutical composition is for oral administration, it may be in the form of a liquid formulation selected from the group consisting of a solution, syrup, suspension or emulsion. When the pharmaceutical composition is an effervescent oral dosage form, it may be in a form selected from the group comprising tablets, granules, powders. When the pharmaceutical composition is in the form of an oral powder or multiparticulate system, it may be in a form selected from the group consisting of beads, granules, minitablets and microparticles. When the pharmaceutical composition is in the form of an orodispersible tablet, it may be in the form of a film, a chewable tablet, a capsule or a chewing gum for medical use.
According to the invention, the pharmaceutical composition may be a pharmaceutical composition for oral administration, e.g. buccal and/or sublingual administration, e.g. selected from the group comprising buccal or sublingual tablets, lozenges, drops, spray solutions.
According to the present invention, the pharmaceutical composition may be a pharmaceutical composition for topical or transdermal administration, for example selected from the group comprising ointments, creams, gels, lotions, patches and foams.
According to the invention, the pharmaceutical composition may be a pharmaceutical composition for nasal administration, for example selected from the group comprising nasal drops, nasal sprays, nasal powders.
According to the present invention, the pharmaceutical composition may be a pharmaceutical composition for parenteral administration, e.g. subcutaneous, intramuscular, intravenous, intraarterial, intracranial, intrathecal. Preferably, the pharmaceutical composition may be a pharmaceutical composition for intra-arterial and/or intracranial administration.
The composition of the invention may also comprise at least one other active ingredient, in particular another therapeutically active ingredient, for example for simultaneous, separate or staggered use over time depending on the galenic formulation used. The other ingredient may be, for example, an active ingredient for use, for example, in the treatment of an appropriate disease that may develop in patients with altered blood brain barrier and/or injury. They may also be pharmaceutical products known to the person skilled in the art, such as antibiotics, anti-inflammatory agents, anticoagulants, neuroprotective agents, acetylcholinesterase inhibitors, antidepressants, antiviral agents.
According to the invention, the composition may be administered, for example, daily, twice daily and weekly. It may be, for example, administered once a day, twice a day, or more.
According to the invention, the composition may be administered, for example, over a period of 1 day to 3 months, for example 2 months. For example, the composition may be administered at a daily administration frequency over a period of 3 months.
The invention also relates to the use of a pharmaceutical composition comprising a biocompatible polymer of formula AaXxYy (I) or AaXxYyZz (II) for the preparation of a medicament for protecting and/or repairing/restoring the blood brain barrier.
The biocompatible polymer is as defined above.
In this embodiment, the term drug is understood to mean a pharmaceutical composition as defined above.
Advantageously, the inventors have shown that biocompatible polymers can unexpectedly accelerate repair/reformation of the blood brain barrier as it changes at the structural and/or functional level. Furthermore, the inventors have shown that biocompatible polymers advantageously and unexpectedly allow functional recovery of the blood brain barrier, in particular recovery of its permeability, regardless of the cause and/or origin of its modification and/or change.
Drawings
FIG. 1 shows the evolution of Blood Brain Barrier (BBB) permeability over time following an ischemic vascular accident; the ordinate corresponds to permeability and the abscissa corresponds to time in hours.
Fig. 2 shows an example of the structure of a biocompatible polymer, such as the structure of compound OTR4132.
Fig. 3 is a bar graph showing BBB permeability evolution in a region of interest studied by MRI. In this figure, the abscissa corresponds to the time in hours or days after cerebral ischemia: 1 hour, 3 hours, 24 hours, 48 hours and 7 days after ischemia. The values obtained correspond to the mean +/-standard deviation. In this figure, the ordinate corresponds to the scale in mm 3 Modified volume of BBB integrity. The values obtained for rats administered with a composition comprising a biocompatible polymer (OTR 4132) are represented by white bars, and the values obtained for rats administered with a control composition are represented by black bars.
Fig. 4 is a bar graph showing BBB permeability after cerebral ischemia by evans blue staining. In this figure, the ordinate indicates the amount of Evan's blue in μg/g brain tissue according to ischemic areas of the central nervous system (i.e. ipsilateral or contralateral). The values obtained for rats administered with a composition comprising a biocompatible polymer (OTR 4132) are represented by grey bars, and the values obtained for rats administered with a control composition are represented by black bars.
Other advantages will be apparent to those skilled in the art from a reading of the following examples, which are given by way of illustration in the accompanying drawings.
Detailed Description
Example 1: use of biocompatible polymers for the treatment of impaired blood brain barrier and restoration of blood brain barrier function
Preparation of A/biocompatible polymers.
The synthesis of biocompatible polymers RGTA is widely described in the prior art, for example in U.S. Pat. No. 7,396,923 titled "Process for the sulfonation of compounds comprising free hydroxyl (OH) groups or primary or secondary amines" and in literature reference Yasunori i. Et al, biomaterials 2011,32:769e 776) and Petit e. Et al, biomacromolecules.254 mar-Apr;5 (2) 445-52[28 ].
Several RGTAs are known and described, including OTR4120, which describe a number of preclinical and clinical publications (based onIs a new branch in matrix therapy-exercise regenerative medicine. Barrittault D, desganges P, meddahi-Pelee A, denoix JM, saffar JL.job bond spin.2017May; 84 (3) 283-292.DOI:10.1016/j.jbspin.2016.06.012[29 ]],/>Or the regenerant mimics heparan sulfate in regenerative medicine: from concept to cure patients Barritt D, gilbert-Sirieix M, rice KL, sineriz F, papy-Garcia D, baudeuin C, desganges P, zake G, saffar JL, van Neck J.Glycoconj J.2017Jun;34 (3) 325-338.DOI:10.1007/s10719-016-9744-5[ 2]]. Compound OTR4131 is a compound comprising a group Z which is a fatty acid, i.e. acetic acid, such as Frescaline g. Et al, tissue Eng Part A2013 Jul;19 (13-14) 1641-53.DOI:10.1089/ten. TEA.2012.0377[30 ]]The random control experiments indicated that +.A.A.A.of the above) based on>Is beneficial for treating race-horse tendinosis. Jacquet-Guibon S, dupays AG, caudry V, crevier-Denoix N, leroy S, sineriz F, chiappini F, barritault D, denoix JM.PLoS one.2018Mar9; 13 (3) e0191796.DOI 10.1371/journ.fine.0191796 [31 ]]. Other compounds are also described in U.S. Pat. No. 3,125,1, in which Z is an amino acid such as phenylalanine (heparan sulfate proteoglycans mediate internalization and proliferation of specific protein pathogenic seeds Holmes BB, deVos SL, kfour N, li M, jacks R, yanamandra K, ouidja MO, brodsky FM, marasa J, bagchi DP, kotzbauer PT, miller TM, pay-Garcia D, diamond Ml. Proc Natl Acad Sci US A2013Aug 13;110 (33): E3138-47.DOI: 10.1073/pnas.130144017110 [32 ]]) Or other hydrophobic compounds (structure activity studies of heparinoids for anti-prion therapy). Ouidja MO, petit E, kerrosME,Ikeda Y,Morin C,Carpentier G,Barritault D,Brugère-Picoux J,Deslys JP,Adjou K,Papy-Garcia D.Biochem Biophys Res Commun.2007Nov 9；363(1):95-100[33])。
B/functional repair of the blood brain barrier using biocompatible polymers
In this example, the effect of the biocompatible polymer RGTA according to the invention on BBB permeability after modification, e.g. after cerebrovascular accident (CVA), was evaluated.
In this example, the rat CVA model was used. It is a1 hour cerebral ischemia, obtained by occlusion of the cerebral artery by the endoluminal route followed by reperfusion. The rats used were male Sprague Dawley rats with an average body weight of 300-350 g. The number of rats used per time was four to six rats per group. In this model, it is well known that the permeability of the BBB gradually increases to peak 24-48 hours after induction of cerebral ischemia (Garrigue et al 2016[6]; sharif et al 2018[16 ]). FIG. 1 shows the change in permeability over time in a model used as described in Abdulahi et al, 2018.
1h, 3h, 24h, 48h and 7 days after cerebral ischemia, contrast medium was injectedThereafter, BBB permeability was evaluated by MRI. The contrast agent does not cross the BBB under physiological conditions. Contrast medium is injected intravenously through the femoral vein. The amount of contrast agent administered by injection was 200. Mu. Mol/kg (Dotarem (registered trademark), guerbet S.A.).
Rats, i.e. four to five animals per group, were treated with biocompatible polymers, i.e. RGTA OTR4132 with a molecular weight of 100,000 to 150,000 da. Fig. 2 shows the structure of the polymer. The biocompatible polymer OTR4132 was administered 1 hour after cerebral ischemia, and the volume of the administered composition comprising OTR4132 at a concentration of 0.5mg/kg was 300 μl/tail vein.
Rats, i.e., four to five animals per group, were treated with a control solution, i.e., physiological serum (0.9% nacl saline solution). The control solution was administered in the same manner as the composition comprising compound OTR4132, i.e. 1 hour after cerebral ischemia, the volume of the composition administered was 250 μl, administered via femoral vein.
The permeability and diffusion of the contrast agent are observed by observation on an image obtained by MRI. The central nervous system region was observed to be located in the brain hemisphere affected by ischemia and in the healthy contralateral hemisphere. The diffusion of contrast agent on the obtained images was determined by MRI analysis using appropriate software (Image J (trademark) (Wayne Rasband, NIMH, maryland, USA)). The diffusion of contrast agent and/or the permeability of the blood brain barrier is shown in fig. 3.
As shown in the graph of fig. 3, rats given contrast agent and control solution exhibited increased blood brain barrier permeability (black bars) 24 hours, 48 hours, and 7 days after CVA; these results are consistent with those obtained in the prior art (Garrigue et al 2016[6 ]). The figure also clearly and unexpectedly shows that treatment of rats with the biocompatible polymer OTR4132 makes it possible to significantly reduce the permeability of the BBB 24 and 48 hours after ischemia in the group of rats treated with RGTA, compared to rats in the ischemic group receiving the control solution. In particular, the results indicate a statistically significant difference between rats treated with the control solution and rats treated with the composition comprising the biocompatible polymer according to the invention (ANOVA followed by a post-hoc HSD test by Tukey, p < 0.05).
The results obtained and illustrated in figure 3 clearly demonstrate that the use of biocompatible polymers according to the invention makes it possible to maintain the integrity of the BBB after CVA. In particular, these results clearly demonstrate that the use of biocompatible polymers according to the invention can protect the BBB, promote its repair, and, in the event of a change/modification of the physiological properties of the BBB, restore the physiological properties and/or reduce its variation.
In addition to the results obtained by MRI, the permeability of the BBB was measured by staining with Evan blue after induction of cerebral ischemia according to the method described in the literature hoc et al, 2018[7 ]. The rats used were male Sprague Dawley rats with an average body weight of 300-350g, and experiments were performed on 11 rats, 5 of which were intravenously injected with 2% concentration of Evan blue (not across the BBB under physiological conditions) 72 hours after cerebral ischemia in a volume of 4ml/kg, i.e. 1.2-1.4ml for rats with body weights of 300-350g, respectively.
Six rats were treated with a biocompatible polymer, RGTA OTR4132 having a molecular weight of 100,000 to 150,000da, administered 1 hour after cerebral ischemia, and the volume of the composition comprising OTR4132 administered by intra-carotid artery at a dose of 2.22 μg was 50 μl.
Five rats were treated with a control solution, i.e. physiological serum (0.9% nacl saline solution) and administered in the same manner as the composition comprising compound OTR4132, i.e. 1 hour after cerebral ischemia, the volume of the composition administered in the carotid artery was 50 μl.
Thirty minutes after administration of evans blue, animals were perfused intraparenchymally with physiological saline, brains removed and hemispheres isolated. The samples were then triturated in phosphate buffered saline and then placed at 4 ℃ in the presence of 60% trichloroacetic acid. The sample was then centrifuged (1,000 g,30 minutes) and the supernatant collected for spectrophotometric reading at 610 nm. Meanwhile, evans blue was prepared in increasing concentration ranges.
The tissue Evan blue present in the collected supernatant was then quantified by spectrophotometry at 610 nm.
Fig. 4 shows the results obtained from individuals. The results obtained in the control animals showed a significant change in BBB permeability in the ipsilateral hemisphere compared to the contralateral hemisphere (2-way ANOVA (p-group=0.1582; p-hemisphere=0.0933; p-group-hemisphere=0.0175), followed by a Tukey HSD post-hoc test p=0.0374). Unexpectedly, no difference was observed between the ipsilateral and contralateral hemispheres of the group of animals treated with biocompatible polymer OTR4132 (2-way ANOVA (p-group=0.1582; p-hemispheres=0.0933; p-group-hemispheres=0.0175), followed by Tukey HSD post-hoc inspection of p=0.9965). Furthermore, this analysis also shows that the BBB change in the ipsilateral hemispheres of animals treated with biocompatible polymer OTR4132 was statistically significantly reduced compared to control animals (2-way ANOVA (p-group=0.1582; p-hemispheres=0.0933; p-group-hemispheres=0.0175), followed by a Tukey HSD post-test p= 0.0439).
This example clearly shows that examples of compositions according to the invention comprising polymers of formula AaXxYy or AaXxYyZz advantageously allow to protect the BBB and/or to restore the physiological properties of the BBB. In particular, this example clearly shows that examples of compositions according to the invention comprising polymers of formula AaXxYy or AaXxYyZz make it possible to maintain the integrity of the BBB after CVA. In particular, these results clearly demonstrate that the use of biocompatible polymers according to the invention can protect the BBB, promote its repair, and, in the event of a change/modification of the physiological properties of the BBB, restore the physiological properties and/or reduce its variation.
Example 2: use of biocompatible polymers for the treatment of alterations in the blood brain barrier and restoration of blood brain barrier function
A75 year old male (75 kg) suffering from a neurological disorder, in particular a cognitive disorder, due to several CVAs indicated by a neurologist, which alters the blood brain barrier, is treated with a biocompatible polymer, i.e. the compound OTR4120, by taking 30ml of a 100 μg/ml OTR4120 aqueous solution daily over 45 days. The administration dose was 3 mg/day/75 kg or 40. Mu.g/kg/day. After administration, the neurologist and the attending or referring physician and the family members of the individual observe an improvement in cognitive performance.
Another individual is an 85 year old female, suffering from serious memory problems, especially difficulty in reading and identifying individuals, especially close relatives (family), inability to write, etc. Individuals diagnosed with Alzheimer's disease with a coefficient of disorder, implying a change in the blood brain barrier (weighing about 60 kg), were treated by sublingual intake of OTR4120 at a dose of 300. Mu.L to 100. Mu.g/ml or 0.5. Mu.g twice weekly. After 6 months of treatment, the individual shows improvement in cognitive function, social relationships, e.g., relationships with her environment, particularly relatives and medical personnel, capable of making phone calls, going out, meeting friends, playing spelling games, etc. These improvements are particularly relevant to the improvement and restoration of blood brain barrier function.
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Claims (14)

1. Use of a pharmaceutical composition comprising a biocompatible polymer of the general formula (I) for the preparation of a medicament for protecting and/or repairing/restoring the blood brain barrier
AaXxYy(I)
Wherein:
a represents glucose, and the component A represents glucose,
x represents R 1 COOR 2 A group, wherein R 1 is-CH 2 -，R 2 Is a group R 21 R 22 Wherein R is 21 Is an anion, R 22 Is a cation selected from the group of alkali metals,
y represents-R 7 SO 3 R 8 Wherein R is 7 Is a bond, R 8 Is an alkali metal selected from the group consisting of lithium, sodium, potassium, rubidium and cesium,
a represents the number of monomers and is defined as,
x represents the degree of substitution of monomer A by the X group,
y represents the degree of substitution of monomer A by the Y group.
2. The use of claim 1, wherein the composition further comprises hyaluronic acid.
3. Use according to claim 1 or 2, wherein X represents a formula-CH 2 -COO - Is a group of (2).
4. Use according to claim 1 or 2, wherein Y represents-SO 3 -a group or-SO 3 -Na + 。
5. The use according to claim 1 or 2, wherein the monomer number "a" is such that the mass of the polymer of formula (I) is greater than or equal to 2,000 daltons.
6. Use according to claim 1 or 2, wherein x is 10% to 150%.
7. The use according to claim 1 or 2, wherein the degree of substitution "y" is from 10% to 170%.
8. The use according to claim 1 or 2, wherein the biocompatible polymer further comprises chemical Z functional groups different from X and Y, which are capable of imparting additional biological or physicochemical properties to the polymer.
9. The use according to claim 8, wherein the degree of substitution of all monomers a represented by "Z" by Z groups is from 1% to 50%.
10. The use according to claim 8, wherein the Z group is a substance capable of imparting better solubility or lipophilicity to the polymer.
11. Use according to claim 8, characterized in that the Z groups are identical or different and are selected from amino acids or fatty acids.
12. Use according to claim 11, wherein the Z group is selected from phenylalanine or acetic acid.
13. The use according to claim 1 or 2, wherein the biopolymer is administered to protect and/or repair/restore the blood brain barrier by: parenterally at a dose of 0.1 to 5mg/kg body weight, and/or orally at a dose of 0.1 to 5mg/kg body weight, and/or at a dose of 0.1 to 100 μg.ml -1 Is administered intracranially at a dose.
14. The use according to claim 2, wherein the concentration of hyaluronic acid is from 1 to 10mg/ml.
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